Decline in the immune system is a feature of human aging. Reduction in naive T cell repertoire to combat novel pathogens stems from decreased function of the thymus where T cells develop. Stage-specific signal transduction and gene expression, resulting from reciprocal cell-cell interactions and locally produced cytokines and hormones, is critical for T cell development. Cues from stromal cells regulate an exquisite balance of proliferation, quiescence, cell-death and cell-fate decisions in developing thymocytes. In turn, thymocytes regulate the maturation of thymic epithelial cells. Understanding this interplay at a molecular level will provide insights that might be translated into novel therapies.